title: Phosphorylation of neuronal Lysine-Specific Demethylase 1LSD1/KDM1A impairs transcriptional repression by regulating interaction with CoREST and histone deacetylases HDAC1/2.
abstract: Epigenetic mechanisms play important roles in brain development, orchestrating proliferation, differentiation, and morphogenesis. Lysine-Specific Demethylase 1 (LSD1 also known as KDM1A and AOF2) is a histone modifier involved in transcriptional repression, forming a stable core complex with the corepressors corepressor of REST (CoREST) and histone deacetylases (HDAC1/2). Importantly, in the mammalian CNS, neuronal LSD1-8a, an alternative splicing isoform of LSD1 including the mini-exon E8a, sets alongside LSD1 and is capable of enhancing neurite growth and morphogenesis. Here, we describe that the morphogenic properties of neuronal LSD1-8a require switching off repressive activity and this negative modulation is mediated in vivo by phosphorylation of the Thr369b residue coded by exon E8a. Three-dimensional crystal structure analysis using a phospho-mimetic mutant (Thr369bAsp), indicate that phosphorylation affects the residues surrounding the exon E8a-coded amino acids, causing a local conformational change. We suggest that phosphorylation, without affecting demethylase activity, causes in neurons CoREST and HDAC1/2 corepressors detachment from LSD1-8a and impairs neuronal LSD1-8a repressive activity. In neurons, Thr369b phosphorylation is required for morphogenic activity, converting neuronal LSD1-8a in a dominant-negative isoform, challenging LSD1-mediated transcriptional repression on target genes.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Toffolo
authors.forename: Francesco
authors.initials: F
authors.lastname: Rusconi
authors.forename: Leda
authors.initials: L
authors.lastname: Paganini
authors.forename: Marcello
authors.initials: M
authors.lastname: Tortorici
authors.forename: Simona
authors.initials: S
authors.lastname: Pilotto
authors.forename: Christopher
authors.initials: C
authors.lastname: Heise
authors.forename: Chiara
authors.initials: C
authors.lastname: Verpelli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Tedeschi
authors.forename: Elisa
authors.initials: E
authors.lastname: Maffioli
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.forename: Elena
authors.initials: E
authors.lastname: Battaglioli
mesh_terms: D000818:Animals; D001923:Brain Chemistry / Q000502:physiology; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D004794:Enzyme Repression; D005091:Exons / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D017930:Genes, Reporter; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D056466:Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics*; D047468:Immunoprecipitation; D007527:Isoenzymes / Q000378:metabolism; D013058:Mass Spectrometry; D016297:Mutagenesis, Site-Directed; D016501:Neurites / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D051381:Rats; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D002843:Chromatin; D056970:Co-Repressor Proteins; D007527:Isoenzymes; D056466:Histone Demethylases; C557089:KDM1A protein, rat; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: KDM1A/LSD1; corepressor; epigenetics; neuronal maturation; transcription